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Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning

Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who pre...

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Autores principales: Sajeev, Mona, Chin, Sharon, Ho, Gladys, Bennetts, Bruce, Sankaran, Bindu Parayil, Gutierrez, Bea, Devanapalli, Beena, Tolun, Adviye Ayper, Wiley, Veronica, Fletcher, Janice, Fuller, Maria, Balasubramaniam, Shanti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162326/
https://www.ncbi.nlm.nih.gov/pubmed/34069211
http://dx.doi.org/10.3390/ijns7020025
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author Sajeev, Mona
Chin, Sharon
Ho, Gladys
Bennetts, Bruce
Sankaran, Bindu Parayil
Gutierrez, Bea
Devanapalli, Beena
Tolun, Adviye Ayper
Wiley, Veronica
Fletcher, Janice
Fuller, Maria
Balasubramaniam, Shanti
author_facet Sajeev, Mona
Chin, Sharon
Ho, Gladys
Bennetts, Bruce
Sankaran, Bindu Parayil
Gutierrez, Bea
Devanapalli, Beena
Tolun, Adviye Ayper
Wiley, Veronica
Fletcher, Janice
Fuller, Maria
Balasubramaniam, Shanti
author_sort Sajeev, Mona
collection PubMed
description Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and progression in myelination. Her clinical phenotype, including protein tolerance, correlated with intermediate MSUD. Molecular analysis of all three genes identified two variants of uncertain significance, c.434-15_434-4del and c.365A>G (p. Tyr122Cys) in the DBT gene. The rate of leucine decarboxylation in fibroblasts was reduced, but not to the extent observed in classical MSUD patients, supporting an intermediate form of MSUD. Previously reported mRNA splicing studies supported a deleterious effect of the c.434-15_434-4del variant. This functional evidence and confirmation that the variants were in trans, permitted their reclassification as pathogenic and likely pathogenic, respectively, facilitating subsequent prenatal testing. This report highlights the challenges in identifying intermediate MSUD by newborn screening, reinforcing the importance of functional studies to confirm variant pathogenicity in this era of molecular diagnostics.
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spelling pubmed-81623262021-05-29 Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning Sajeev, Mona Chin, Sharon Ho, Gladys Bennetts, Bruce Sankaran, Bindu Parayil Gutierrez, Bea Devanapalli, Beena Tolun, Adviye Ayper Wiley, Veronica Fletcher, Janice Fuller, Maria Balasubramaniam, Shanti Int J Neonatal Screen Case Report Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and progression in myelination. Her clinical phenotype, including protein tolerance, correlated with intermediate MSUD. Molecular analysis of all three genes identified two variants of uncertain significance, c.434-15_434-4del and c.365A>G (p. Tyr122Cys) in the DBT gene. The rate of leucine decarboxylation in fibroblasts was reduced, but not to the extent observed in classical MSUD patients, supporting an intermediate form of MSUD. Previously reported mRNA splicing studies supported a deleterious effect of the c.434-15_434-4del variant. This functional evidence and confirmation that the variants were in trans, permitted their reclassification as pathogenic and likely pathogenic, respectively, facilitating subsequent prenatal testing. This report highlights the challenges in identifying intermediate MSUD by newborn screening, reinforcing the importance of functional studies to confirm variant pathogenicity in this era of molecular diagnostics. MDPI 2021-05-14 /pmc/articles/PMC8162326/ /pubmed/34069211 http://dx.doi.org/10.3390/ijns7020025 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Sajeev, Mona
Chin, Sharon
Ho, Gladys
Bennetts, Bruce
Sankaran, Bindu Parayil
Gutierrez, Bea
Devanapalli, Beena
Tolun, Adviye Ayper
Wiley, Veronica
Fletcher, Janice
Fuller, Maria
Balasubramaniam, Shanti
Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning
title Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning
title_full Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning
title_fullStr Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning
title_full_unstemmed Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning
title_short Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning
title_sort challenges in diagnosing intermediate maple syrup urine disease by newborn screening and functional validation of genomic results imperative for reproductive family planning
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162326/
https://www.ncbi.nlm.nih.gov/pubmed/34069211
http://dx.doi.org/10.3390/ijns7020025
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